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Rings In (Candidate) Drugs - Case Stories

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Selected project impacts from over a decade of using insights from computational chemistry Focus on heterocyclic rings in candidate drugs discovered at AstraZeneca/CVMD and the strategies used in their design. The case stories will include a wide variety of examples, such as (i) replacing unwanted functional groups like acids and esters with heterocyclic rings, (ii) using rings for geometrical reasons and (iii) using heterocyclic rings to fine-tune electrostatics to obtain improved properties. In most cases the key computational approach for designing candidate drugs has been the use of shape and electrostatic comparisons between molecules. The role of luck is also discussed.

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Rings In (Candidate) Drugs - Case Stories

  1. 1. Rings in (Candidate) Drugs – Case Stories Jonas Boström, CVMD iMED, AstraZeneca R&D, Mölndal, Sweden jonas.bostrom@astrazeneca.com
  2. 2. A Five Case Story Rollercoaster key computational approach for designing candidate drugs often the use of shape and electrostatic comparisons between molecules 1) for (purely) geometrical reasons 2) replacing unwanted functional groups (acids and esters) 3) to fine-tune electrostatics for improved properties 2000 CB1 scaffold-hopping –> only geometry matters 1 LXR scaffold-hopping and ”luck” 1 P2Y12 ester replacement heterocycle 2 NOFI acid bioisostere – > heterocycle 2 now ”Matched-Pair Project X” heterocyclic electrostatics  improved properties 3 Heterocyclic rings…
  3. 3. CB1 scaffold-hopping –> only geometry matters? CB1 antagonists – a “me-too” project 2000 now
  4. 4. Rimonabant (Sanofi-Aventis):  a selective high-affinity CB1 inverse agonist  inhibits food intake in rats, mice, marmosets and man  was in clinical studies for treatment of obesity Cannabis increases food intake  Marijuana users are often overweight  inverse agonist (or antagonist)? No CB1 protein X-ray structure  ligand-based design CB1 antagonists – a “me-too” project Our scaffold-hopping strategy Replace the pyrazole scaffold in Rimonabant with different heterocyclic rings: thiazoles, pyrroles and pyrazines Check chemical feasibility Check shape-complementarity to the putative bioactive conformation of Rimonabant Mini-libraries of 20 cpds/class were synthesized to evaluate the different classes. Boström et al. “Scaffold hopping, synthesis and structure–activity relationships of 5,6-diaryl-pyrazine-2-amide derivatives: A novel series of CB1 receptor antagonists”. Bioorganic and Medicinal Chemistry, 2007,15, 4077.
  5. 5. Shape-Based Scaffold-Hopping All classes virtually identical to Rimonabant Shape-overlays (ROCS). Tanimoto> 0.9 All central scaffolds “work”, and are electronically different – essential for geometrical reasons? (compounds very lipophilic) AZ-”pyrazines” AZ-”pyrroles” AZ-”thiazoles” 19 cpds synthesized 10 < 100nM (4 < 10nM) 33 cpds synthesized 17 < 100nM (4 < 10nM) 17 cpds synthesized 4 < 100nM (2<10nM) + from the literature/patents imidazoles, triazoles, ring-closures, etc
  6. 6. Withdrawal of marketing authorization for Rimnabant (FDA/EMEA). AZ Project stopped after candidate drug nomination. Effect of AZ-”pyrazine” and Rimonabant on body-weight (BW) in cafeteria-diet, obese mice. Cpd5e CB1 Summary AZ-”pyrazine” AZ-”pyrazine” any heterocycle ? “The function of the central scaffold is not to make any direct interactions with the cannabinoid receptor, but rather to place the substituted phenyl rings and the N- carboxyamide fragments in an optimal 3D orientation” Boström et al. “Scaffold hopping, synthesis and structure–activity relationships of 5,6-diaryl-pyrazine-2-amide derivatives: A novel series of CB1 receptor antagonists”. Bioorganic and Medicinal Chemistry, 2007,15, 4077.
  7. 7. LXR scaffold-hopping and ”luck” 2015 LXR “Lucky” Scaffold-hopping The Role of Conformational Analysis in the Design of LXR Agonists
  8. 8. “T0901317” 24 nM “AZ HTS hit” 70 nM A novel series of potent nonsteroidal LXR agonists LXR “Lucky” Scaffold-hopping Liver X Receptor (LXR) agonists for the treatment of atherosclerotic cardiovascular disease Conformational ensembles OMEGA, shape-matching ROCS accessed via an interactive web-interface The design of a novel series LXR agonists from a conformational analysis of two compounds: Molecular Alignments
  9. 9. LXR Scaffold-hopping Systematic pair-wise shape comparison of low-energy conformation gave a few alignments Conformational ensembles OMEGA, shape-matching ROCS accessed via an interactive web-interface hydrophob hydrophob acceptor acceptor hydrophob It seemed to make sense… Tanimoto: 0.86 add one “H-bond acceptor” Visual inspection of these favored the alignment which the N-substituted side-chains and the phenyl rings (pharmacophores/SAR) are all in approximate coincidence.
  10. 10. Then came the LXR X-ray structure… The right geometry (and potency)…but for the wrong reason… Conformation was essentially correct, but the pose wasn’t PDB: 1PQC
  11. 11. LXR X-ray structures were solved… isothiazol-3(2H)-one 1,1-dioxides containing scaffold superior to HTS hit series A novel series of potent nonsteroidal LXR agonists “designed” 17 nM lucky scaffold hopping expansion virtually identical Project stopped after candidate drug nomination “AZ HTS hit” 70 nM Boström et al. “Do structurally similar ligands bind in a similar fashion?”. J.Med. Chem., 2006, 49, 6716.
  12. 12. P2Y12 ester replacement heterocycle 2 P2Y12 – ethylester replacements
  13. 13.  Easy chemistry – library design 160 cpds with variation of substituents on pyridine and phenyl SAR – affinity range for compounds binding/GTPgS Zetterberg, Bach, Boström ”A novel series of piperazinyl-pyridine ureas as antagonists of the purinergic P2Y12 receptor” Bioorg. Med. Chem. Lett. 21 (2011) 2877–2881 SAR Thrombosis is the formation of a blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. May cause stroke and sudden death. HTS  several hits Among the most interesting: the ”piperazinylpyridines” series P2Y12 – Prevention of Thrombosis
  14. 14. Ethyl ester functionality a potential liability • generally high in vivo clearance due to hydrolysis P2Y12 – ethylester replacements Can we replace the ester while retaining activity? …and increase metabolic stability by replacing the ethyl ester with bioisosteres
  15. 15. P2Y12 – ethylester replacements Non-cyclic ester replacements – inactive in P2Y12 binding and GTPgS
  16. 16. Design Strategy Replace ethylester functionality by hydrolytically stable 5-membered heterocycle Around 20 five-membered heterocyclic systems synthetically attainable evaluated. Shape and electrostatics to classify similarity to ethyl ester Heterocyclic Rings as Ethylester Replacements “good” +1 “mediocre” +4 “bad” + a few Ten compounds (structures shown) made and tested. Bach, Boström, Zetterberg “5-Alkyl-1,3-oxazole derivatives of 6-amino-nicotinic acids as alkyl ester bioisosteres are antagonists of the P2Y12 receptor” Future Med. Chem., 2013, 5(17), 2037-2056
  17. 17. P2Y12 Results Oxazoles a suitable replacement shape and electrostatics (ItsElectric*) * ItsElectric and EON (OpenEye) are based on the same toolkit (ZAP) and theory (PB electrostatic potentials).
  18. 18. correctly suggests that 5-methyl-oxazole better than the 4-methyl oxazole Conformations where possible ring-substitutents overlayed with the ethyl moiety selected weak H-bond acceptor strong H-bond acceptor Shape & Electrostatic complementarities vdW
  19. 19. P2Y12 Summary The potential metabolic instability of ethyl esters was addressed by shape and electrostatics rankings to select 5-membered heterocycles for synthesis. Hydrolytically stable 5-methyl derivatives were identified as P2Y12 antagonists. The physical nature of the shape and electrostatic similarity approach ensured that a non-obvious substructure change could be incorporated to mimic the behavior of the ethyl ester functionality. Not likely that other commonly used similarity measures (FPs, MCSS), would have predicted the oxazole fragment as similar to the ethyl ester, let alone correctly suggesting that the 5-methyl- oxazole was a better replacement for the ethyl ester than the 4-methyl oxazole. The levels of clearance and bioavailability made the oxazoles series attractive compounds for further development. The ester subseries made it to the clinic – but lack of efficacy
  20. 20. …a P2Y12 X-ray structure was published (and PDB deposited) last year P2Y12 Post-Summary
  21. 21. Where’s the H-bond donor? Ethylester fits tightly, and no room for ”missing” waters. SER-156 could adopt another rotamer (<4.0Å hbond) to carbonyl oxygen No interaction for ether oxygen (making sense…) Electron density quality P2Y12 Post-Summary PDB 4ntj (Resolution 2.6Å)
  22. 22. “NOFI” heterocyclics as carboxylic acid isosteres Electrostatic Similarities 2000 NOFI acid bioisostere – > heterocycle 2
  23. 23. Protein-protein interfaces provide an important class of drug targets receiving increased attention. The typical design strategy usually involves large molecules (peptides and macrocycles) A simplistic(!) view of the mechanism Novel Oral Fibrinolysis Inhibitors (NOFI) Boström et al “Potent Fibrinolysis Inhibitor Discovered by Shape and Electrostatic Complementarity to the Drug Tranexamic Acid” J.Med.Chem. 2013, 56, 3273 Fibrinolysis is a process that prevents blood clots from growing and becoming problematic
  24. 24. X-ray crystallography – structures known pdb: 1ceb (and 1cea) Crystal structures of the recombinant Kringle 1 domain of human plasminogen in complexes with the ligands EACA and TXA (Mathews et al. Biochemistry, 1996, 35, 2567–2576) Fibrinolysis Inhibition
  25. 25. Project goal: identify novel compounds which can be given at lower doses and less frequently than TXA, by improving some combination of the efficacy, bioavailability and clearance. TXA and EACA are well-established clinical agents used to reduce blood-loss following surgery and trauma and to treat heavy menstrual bleeding, mild haemophilia and certain forms of von Willebrands disease Tranexamic acid (TxA) EACA Modest potency and non-optimal pharmacokinetic properties leading to inconvenient dosing (up to 6 g per day). Associated side-effects are also nausea and vomiting. This clearly limits their use and there is consequently an unmet need for new inhibitors of plasminogen with a more convenient dosing and a more acceptable side-effect profile. Lysine analoges: Two Fibrinolysis Inhibitors on the Market
  26. 26. Zooming in on TXA in complex with the recombinant kringle-1 domain of human plasminogen … prominent electrostatic features zwitterionic... pdb: 1ceb (TxA) pdb: 1cea (EACA) Shape-based approaches often successful in virtual screening. In this case not be sufficiently discriminatory due to the simple molecular framework of the zwitterion TXA. This motivated us to compare electrostatic potentials
  27. 27. Low-throughput screening assay for testing putative blood clotting agents; select a small set of compounds Shape-based screening not sufficiently discriminatory due to simple molecular framework of TXA At the time, pre-filtering was a necessity (electrostatic calculations not fast enough) “De-crapping” and visual inspection Virtual Screen Strategy
  28. 28. Virtual Screening – Results 68 compounds screened – ‘only’ one hit Remaining compounds selected were either weakly active or inactive. VS Clot-Lysis plasma assay 0.8 µMClot-Lysis plasma assay 3.1 µM The potency of the lead compound 4-PIOL was found to be four times that of TXA, the current drug widely used in the clinic. Surprising that such an active compound from such as a small set of measurements was discovered.
  29. 29. Isoxazolone a bioisostere Visual inspection of the hydrogen-bonding network in the ligand−protein complex indicates that 4- PIOL and TXA bind in their zwitterionic forms (modelled in their neutral state). The shape of the binding site is well-defined, with both ligands filling the binding site. isoxazolone as a carboxylic acid bioisostere (~5 times potent) GABA 33nM GABA 6nM * Using ligand-based approach ROCS/EON isoxazolone
  30. 30. ClotLys (Plasma): 0.8µM pKa acid: 4.0 ClotLys (Plasma): 1.3µM pKa acid: 4.1 ClotLys (Plasma): 4.0µM pKa acid: 8.2 ClotLys (Plasma): 6.3µM pKa acid: 7.0 ClotLys (Plasma): >100µM pKa acid: 4.0 Tetrazole the most common carboxylic acid isostere, but is an imperfect surrogate. None more potent Acquired and/or synthesized heterocyclic compounds Few similar compounds to 4-PIOL available internally and externally at the time*
  31. 31. Acquired and/or synthesized heterocyclic compounds ClotLys (Plasma): 0.8µM pKa acid: 4.0 ClotLys (Plasma): 1.3µM pKa acid: 4.1 ClotLys (Plasma): 4.0µM pKa acid: 8.2 ClotLys (Plasma): 6.3µM pKa acid: 7.0 ClotLys (Plasma): >100µM pKa acid: 4.0 false positive base acid tetrazole shorter
  32. 32. Tetrazole vs isoxazolone 8.0Å (vs 9.3Å) base acidtoo short
  33. 33. DMPK Profiling The lipophilicity of 4-PIOL was determined to be low (logD < 0), an atypical liability. Hydrophilicity can be disadvantageous, mainly due to poor cell permeability (Caco-2), resulting in unfavorable DMPK characteristics in general and suggestive of difficulties with creating a successful oral formulation The pKa of the basic amines in TXA and 4- PIOL are similar (9.7 and 10.5), and that the acid pKa’s are nearly identical (4.1 and 4.0).
  34. 34. Summary • 4-PIOL was identified as a four-fold more potent fibrinolysis inhibitor than TXA using a low throughput screen where the compound selection was made using computational techniques. • The key computational approach to our contribution for finding the right lead compound was shape and electrostatic comparisons between molecules. • It is clear that the computational approach described in the present work identified a non- trivial bioisostere of TXA as a high quality lead for a subsequent lead optimization program. • It is difficulty to accurately assigning correct ionization states to a large collection of molecules, supporting our approach of modeling all compounds in their neutral state. • 4-PIOL served as an excellent starting point for subsequent lead optimization.
  35. 35. Analogs to 4-PIOL selective against GABA-A, with good cell permeability and retained potency with respect to plasminogen inhibition were designed, by means of two approaches, keeping the graph/framework. • A “methyl-scanning” exercise on 4-PIOL and • molecular overlays of two structurally different series Leading to the same observation: substitution of the 2’-position increases GABA-A selectivity and improved cell permeability Lead Optimization Challenging synthetic chemistry issues were solved Project stopped after candidate drug nomination. “4-PIOL served as an excellent starting point for subsequent lead optimization” * Concerns over commercial value especially after Lysteda (TxA in a sustained slower-release formulation) launch in US.
  36. 36. Molecular Matched-Pair Project X ”Matched-Pair Project X” fine-tune heterocyclic electrostatics  improved properties 3 https://twitter.com/jmedchem background from MMP oxadiazole paper: Boström et al J. Med. Chem., 2012, 55, 1817
  37. 37. • “Molecules that differ only by a small structural change” (remainder of the molecule is exactly the same). For example • The assumption underlying the matched-pair approach is that it is easier to predict differences in the values of a property than it is to predict the value of the property itself (one reason is cancellation of errors). • The observation of an effect across several chemical series increases our confidence that the effect is real -> general “rules of thumbs” -> future design • One limitation is that it can only make predictions about structural features that have precedent in the given assay. What Are Molecular Matched-Pairs? Prazosin Terazosin Solubility: 1.1 mg/ml Solubility: 28.1 mg/ml
  38. 38. Oxadiazoles in an in-house AZ project O O N N R1R2 O N N O R1R2 Binding Affinity: 80 nM Log D: 3 Solubility: NA HLM Clint: 20 µl/min/mg hERG: 2 µM Binding Affinity: 40 nM Log D: 2 Solubility: 100 mM HLM CLint: 10 µl/min/mg hERG: 10 µM 1,3,4-oxadiazoles showed better properties than 1,2,4-oxadiazoles in terms of lipophilicity, solubility, HLM Clint and hERG Goal: to develop a better understanding for the generality of the observed effects, as well as if possible rationalize the effect. 1,3,4-oxadiazoles1,2,4-oxadiazoles
  39. 39. Oxadiazoles are five-membered heterocycles containing two carbons, two nitrogens and one oxygen atom and they exist in several different regioisomeric forms R' O N N R'' R' N O N R'' R' N N O R'' R' N N O R'' 1,2,4-oxadiazoles 1,3,4-oxadiazole 1,2,5-oxadiazole CSD: NAXDIZ CSD: ZZZTQC01 Side chains (R-groups) will have the same exit vector for 1,2,4 and 1,3,4 regioisomers: same overall shape (but the 1,2,5 regioisomers differs)
  40. 40. Year Frequencyofoccurrenceofoxadiazoles inPharmaceuticalPreparations Oxadiazoles in drug projects Oxadiazole rings are used in drug discovery programs for different purposes • contributing to the binding interactions with the target. • modulates molecular properties through its position on the periphery of the molecule • oxadiazoles has been used as replacements for carbonyl containing compounds (esters, carbamates, hydroxamic esters) • as linker to orient its substituents appropriatly. N S N H N N O O O O N N OH ONO N F 1 (zibotentan) 2 (ataluren) Structures of oxadiazole compounds in late stage clinical development or launched F N H O N N O OH N H O NN O 3 (raltegravir)
  41. 41. Oxadiazole data set Using query-specific matched-pair tool 150 pairs. The compounds essentially show the same characteristics as compounds with typical drug-like properties. The data set covers molecules with different ionization states at physological pH; and several structural series; ~25 clusters. ClogP H-bond don+acc MW
  42. 42. Check differences in lipophilicity ordered exp. logD for the 148 matched-pairs 1,3,4-oxadiazole are systematically less lipophilic than their 1,2,4-oxadiazole partner by one log unit R' O N N R''R' N N O R'' 1,2,4-oxadiazoles 1,3,4-oxadiazole The median logD value for the 1,2,4-isomers is 4.4, whereas it is 3.2 for the 1,3,4-isomers. y = 0.99 + 1.06*x r2 = 0.97 Boström et al ”Oxadiazoles in Medicinal Chemistry” J. Med. Chem., 2012, 55, 1817
  43. 43. Matched Pairs Consequences Lipophilicity is a cardinal property in drug discovery. It generally affects many other properties relevant in lead optimization. How would the difference in lipophilicity between the oxadiazole regioisomers impact other molecular properties? We investigated for example:  Solubility  hERG (and pKa)  CYP inhibition  HLM CLint Desiredproperty Lipophilicity/undesired property 1 2 3 ?
  44. 44. Impact on solubility (subset of 55 pairs) Lipophilicity can influence many other molecular properties, and perhaps the most obvious connection exists between lipophilicity and solubility. R2=0.4 N=116 In general the 1,3,4-oxadiazole is more soluble than the 1,2,4-oxadiazole partner Boström et al ”Oxadiazoles in Medicinal Chemistry” J. Med. Chem., 2012, 55, 1817
  45. 45. In addition, the 1,3,4-oxadiazoles generally show better metabolic stability, in terms of lower HLM CLint values (34 matched-pairs). Impact on CYP inhibition For various CYP enzymes the inhibitory potency of the less polar 1,2,4-oxadiazole derivatives is typically more pronounced than that of the more polar 1,3,4-conterparts; this is particularly true for CYP3A4 (recognizing lipophilic substrates) and CYP1A2 (recognizing planar heterocycles). Boström et al ”Oxadiazoles in Medicinal Chemistry” J. Med. Chem., 2012, 55, 1817
  46. 46. Inhibition of the hERG channel can trigger Torsades de Pointes and arrhythmia One design strategy to reduce hERG inhibition is to decrease lipophilicity. In the majority of cases (N=11), the less lipophilic isomer (1,3,4) is also less potent at hERG. All matched pairs in this subset have a basic functionality near the oxadiazole unit. There’s little or no change in pKa upon switching between the regioisomers. That is, the regioisomers do not have a significant effect on the basicity of the nearby groups. Impact on hERG Boström et al ”Oxadiazoles in Medicinal Chemistry” J. Med. Chem., 2012, 55, 1817
  47. 47. Using electrostatics to rationalize Why are 1,3,4-oxadiazole less lipophilic? Ask your MedChemists (none knew) and calculate… Dipole calculations at B3LYP/6-31G**. Experimental data confirms. Kenny P. et al. J. Med. Chem. 2008, 51, 3720–3730, and Kenny P J. Chem. Soc. Perkin Trans 2 1994, 199-202 1,3,4-oxadiazole show significantly larger dipoles than their 1,2,4-oxadiazole partner The greater the dipole the greater polarity. N ON O N N Minimized molecular electrostatic potential (Vmin) has been shown to be an effective predictor of the of hydrogen bond acceptors - hydrogen bond acceptor strength changes and moves around
  48. 48. Other (unexpectedly) large differences  thiadiazole regioisomers  THF vs furan We have for example investigated:
  49. 49. Thiadiazoles regioisomeric pairs Calculated electrostatics show analogous differences to oxadiazole regioisomers (3.7 vs 2.5D) although the difference is slightly smaller (3.3 vs 2.6D). In thiadiazoles the oxadiazole oxygen atom is ‘replaced’ by a sulfur atom Prediction: a 1:1 relationship between regioisomeric pairs, and that the 1,3,4- thiadiazoles is less lipophilic than 1,2,4 regioisomers. N SN S N N 3.3 D 2.6 D level of theory: HF/3-21G* exit vectors differ somewhat
  50. 50. 0 1 2 3 4 5 6 7 8 0 1 2 3 4 5 6 7 8 explogD 1,2,4-thiadiazoles exp logD 1,3,4-thiadiazoles Differences in lipophilicity 1,3,4-thiadiazole are in general less lipophilic than their 1,2,4-thiadiazole partner R' S N N R''R' N N S R'' 1,2,4-oxadiazoles 1,3,4-oxadiazole R2=0.92 logD The median logD value for the 1,2,4-isomers is 3.2, whereas it is 2.3 for the 1,3,4-isomers. N = 33 ordered exp. logD for the 80 compounds 1,2,4-thiadiazoles 1,3,4-thiadiazoles
  51. 51. Alpha-blocker Solubility: 1.1 mg/ml Log D (shake-flask): 1.8 ACDlogD: 0.0 clogP: 2.0 Alpha-blocker Solubility: 28.1 mg/ml Log D (shake-flask): 0.9 ACDlogD: -1.0 clogP: 2.2 A “me-too” observation: furan vs THF Modification of the hybridization state of carbon atoms can be useful to control molecular properties. Prazosin (Minipress™) – Terazosin (Hytrin™) serves as a matched-pair “me-too” example.* * Water solubility for Terazosin increases significantly when going from furan to THF. As a result, improved bioavailability (90% vs 57%) and half-life (2–3 times) afford longer duration of action, and allow once-daily administration. In addition, there is a safety concern associated with furans, since they are often anticipated to be carcinogentic in humans. Giordanetto, Boström and Tyrchan “Follow-on drugs: how far should chemists look?” Drug Discovery Today, 2011, 16 (15-16),722-732. (doi:10.1016/j.drudis.2011.05.011) Prazosin US Reg Date: 1976-06-23 Terazosin US Reg Date: 1987-08-07
  52. 52. Furan vs tetrahydrofurans: Dsolubility average pSolubility: 4.0 (100µM)average pSolubility: 4.7 (20µM) D pSol: 0.7 A data set of 50 matched-pairs – measure aqueous solubility for the 100 compounds The THF containing compound is more soluble in 85% of the matched-pairs. THF pSolubility pSolubility (furan) The observered difference in solublity for furan/THF pairs seems to be general. R R
  53. 53. Possible rationale for differences Larger dipole for THF than furan – the greater the dipole the greater polarity. The aromaticity in furan obviously makes it different from ethers, especially compared to more strained systems like oxatanes and tetrahydrofurans. Consequently tetrahydrofurans seem to be less lipophilic than their open-chain ether partners. Furan: 0.6 Debye THF: 1.7 Debye FURAOX LIBVIC Different geometries – “escaping flatland” two matched-pairs found in CSD A forgotten furan-bioisoster? Furan-to-Thiophene/Benzene is way more frequent than furan-to-THF.
  54. 54. Matched-Pairs Summary  It can be very powerful to use molecular matched-pairs in drug design. • Intuitive, interpretable and can provide data-driven, interpretable guidelines for design/analysis • Can extract tacit knowledge from accumulated data beyond series, projects and departments  Analyzing 1,2,4- and 1,3,4-oxadiazole regioisomers revealed systematic trends  the 1,3,4-oxadiazole isomer show an order of magnitude of lower logD, compared to the 1,2,4  the favorable effect is also observed in increased aqueous solubility, lower HLM Clint and hERG.  The distinct profile difference is likely due to their different charge distributions.  Methodology can be used to generalize other important properties used for decision-making.  thiadiazoles regioisomers, THF vs furan.  direct impact in in-house AZ projects.
  55. 55. Thanks to all my colleagues! key computational approach for designing candidate drugs often the use of shape and electrostatic comparisons between molecules 1) for (purely) geometrical reasons 2) replacing unwanted functional groups (acids and esters) 3) to fine-tune electrostatics for improved properties 2000 CB1 scaffold-hopping –> only geometry matters 1 LXR scaffold-hopping and ”luck” 1 P2Y12 ester replacement heterocycle 2 NOFI acid bioisostere – > heterocycle 2 now ”Matched-Pair Project X” heterocyclic electrostatics  improved properties 3 Heterocyclic systems needs special attention – a large number of combinations